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  • 1.
    Alehagen, Urban
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Vorkapic, Emina
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Ljungberg, Liza
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Gender difference in adiponectin associated with cardiovascular mortality2015In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 16, no 9Article in journal (Refereed)
    Abstract [en]

    Background: It is important to identify cardiovascular diseases in patients at high risk. To include genetics into routine cardiological patients has therefore been discussed recently. We wanted to evaluate the association between high-molecular weight adiponectin and cardiovascular risk, and secondly in the same population evaluate if specific genotype differences regarding risk could be observed, and thirdly if gender differences could be seen. Method: Four hundred seventy-six elderly participants recruited from a rural community were included. All participants underwent a clinical examination, echocardiography, and blood sampling and the single nucleotide polymorphism (SNP) (rs266729) of adiponectin was analysed. Follow-up time was 6.7 years. Results: Those with high serum concentration of adiponectin had a more 2 fold increased cardiovascular risk, and it might be that females exhibits even higher risk where a more than 5 fold increased risk could be seen. The result could be demonstrated even in a multivariate model adjusting for well-known clinical risk factors. However, as the sample size was small the gender differences should be interpreted with caution. In the genotype evaluation the C/C carriers of the female group had a more than 9-fold increased risk of cardiovascular mortality, however the confidence interval was wide. Such genotype difference could not be found in the male group. Conclusion: High level of adiponectin was associated with increased cardiovascular risk. Also a gender difference in the genotype evaluation could be seen where the C/C carriers obtained higher risk in the female group but not in the male group. Thus, in order to identify patients at risk early, genetic analyses may add to the armamentarium used in the clinical routine. However, information should be regarded as hypothesis generating as the sample size was small and should stimulate further research in individualized cardiovascular prevention and treatment.

  • 2.
    Bertorello, Alejandro M.
    et al.
    Karolinska Institute, Sweden.
    Pires, Nuno
    Bial Portela and Ca SA, Portugal.
    Igreja, Bruno
    Bial Portela and Ca SA, Portugal.
    Joao Pinho, Maria
    University of Porto, Portugal.
    Vorkapic, Emina
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Karolinska Institute, Sweden.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Karolinska Institute, Sweden.
    Wikstrom, Johannes
    AstraZeneca RandD, Sweden.
    Behrendt, Margareta
    AstraZeneca RandD, Sweden.
    Hamsten, Anders
    Karolinska Institute, Sweden.
    Eriksson, Per
    Karolinska Institute, Sweden.
    Soares-da-Silva, Patricio
    Bial Portela and Ca SA, Portugal; University of Porto, Portugal.
    Brion, Laura
    Karolinska Institute, Sweden.
    Increased Arterial Blood Pressure and Vascular Remodeling in Mice Lacking Salt-Inducible Kinase 1 (SIK1)2015In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 116, no 4, p. 642-U190Article in journal (Refereed)
    Abstract [en]

    Rationale: In human genetic studies a single nucleotide polymorphism within the salt-inducible kinase 1 (SIK1) gene was associated with hypertension. Lower SIK1 activity in vascular smooth muscle cells (VSMCs) leads to decreased sodium-potassium ATPase activity, which associates with increased vascular tone. Also, SIK1 participates in a negative feedback mechanism on the transforming growth factor-beta 1 signaling and downregulation of SIK1 induces the expression of extracellular matrix remodeling genes. Objective: To evaluate whether reduced expression/activity of SIK1 alone or in combination with elevated salt intake could modify the structure and function of the vasculature, leading to higher blood pressure. Methods and Results: SIK1 knockout (sik1(-/-)) and wild-type (sik1(+/+)) mice were challenged to a normal-or chronic high-salt intake (1% NaCl). Under normal-salt conditions, the sik1(-/-) mice showed increased collagen deposition in the aorta but similar blood pressure compared with the sik1(+/+) mice. During high-salt intake, the sik1+/+ mice exhibited an increase in SIK1 expression in the VSMCs layer of the aorta, whereas the sik1(-/-) mice exhibited upregulated transforming growth factor-beta 1 signaling and increased expression of endothelin-1 and genes involved in VSMC contraction, higher systolic blood pressure, and signs of cardiac hypertrophy. In vitro knockdown of SIK1 induced upregulation of collagen in aortic adventitial fibroblasts and enhanced the expression of contractile markers and of endothelin-1 in VSMCs. Conclusions: Vascular SIK1 activation might represent a novel mechanism involved in the prevention of high blood pressure development triggered by high-salt intake through the modulation of the contractile phenotype of VSMCs via transforming growth factor-beta 1-signaling inhibition.

  • 3.
    Folkesson, Maggie
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Vorkapic, Emina
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Gulbins, Erich
    University of Duisburg-Essen, University of Cincinnati.
    Japtok, Lukasz
    The department of Toxicology, Institute of Nutritional Science, University of Potsdam.
    Kleuser, Burkhard
    The department of Toxicology, Institute of Nutritional Science, University of Potsdam.
    Welander, Martin
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Inflammatory cells, ceramides, and expression of proteases in perivascular adipose tissue adjacent to human abdominal aortic aneurysms2017In: Journal of Vascular Surgery, ISSN 0741-5214, E-ISSN 1097-6809, Vol. 65, no 4, p. 1171-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Abdominal aortic aneurysm (AAA) is a deadly irreversible weakening and distension of the abdominal aortic wall. The pathogenesis of AAA remains poorly understood. Investigation into the physical and molecular characteristics of perivascular adipose tissue (PVAT) adjacent to AAA has not been done before and is the purpose of this study.

    METHODS AND RESULTS: Human aortae, periaortic PVAT, and fat surrounding peripheral arteries were collected from patients undergoing elective surgical repair of AAA. Control aortas were obtained from recently deceased healthy organ donors with no known arterial disease. Aorta and PVAT was found in AAA to larger extent compared with control aortas. Immunohistochemistry revealed neutrophils, macrophages, mast cells, and T-cells surrounding necrotic adipocytes. Gene expression analysis showed that neutrophils, mast cells, and T-cells were found to be increased in PVAT compared with AAA as well as cathepsin K and S. The concentration of ceramides in PVAT was determined using mass spectrometry and correlated with content of T-cells in the PVAT.

    CONCLUSIONS: Our results suggest a role for abnormal necrotic, inflamed, proteolytic adipose tissue to the adjacent aneurysmal aortic wall in ongoing vascular damage.

  • 4.
    Gacic, Jelena
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology.
    Vorkapic, Emina
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Slind Olsen, Renate
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. County Hospital Ryhov, Sweden.
    Söderberg, Daniel
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Gustafsson, Therese
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Geffers, Robert
    Helmholtz Centre Infect Research, Germany.
    Skoglund, Karin
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Matussek, Andreas
    County Hospital Ryhov, Sweden.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Imatinib reduces cholesterol uptake and matrix metalloproteinase activity in human THP-1 macrophages2016In: Pharmacological Reports, ISSN 1734-1140, E-ISSN 2299-5684, Vol. 68, no 1, p. 1-6Article in journal (Refereed)
    Abstract [en]

    Background: Imatinib mesylate (Glivec, formerly STI-571) is a selective tyrosine kinase inhibitor used for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. However, there are reports suggesting that imatinib could be atheroprotective by lowering plasma low-density lipoprotein (LDL). Aim: To investigate the potential inhibitory effect of imatinib on cholesterol uptake in human macrophages as well as its effect on matrix metalloproteinase (MMP) activity. Methods and results: Uptake of fluorescence-labeled LDL was analyzed using flow cytometry. Macrophages treated with imatinib showed a 23.5%, 27%, and 15% decrease in uptake of native LDL (p < 0.05), acetylated LDL (p < 0.01), and copper-modified oxidized LDL (p < 0.01), respectively. Gel based zymography showed that secretion and activity of MMP-2 and MMP-9 were inhibited by imatinib. Using GeneChip Whole Transcript Expression array analysis, no obvious gene candidates involved in the mechanisms of cholesterol metabolism or MMP regulation were found to be affected by imatinib. Instead, we found that imatinib up-regulated microRNA 155 (miR155) by 43.8% and down-regulated ADAM metallopeptidase domain 28 (ADAM28) by 41.4%. Both genes could potentially play an atheroprotective role and would be interesting targets in future studies. Conclusion: Our results indicate that imatinib causes post-translational inhibition with respect to cholesterol uptake and regulation of MMP-2 and MMP-9. More research is needed to further evaluate the role of imatinib in the regulation of other genes and processes. (c) 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.

  • 5.
    Slind Olsen, Renate
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. County Hospital Ryhov, Sweden.
    Lindh, Mikael
    County Hospital Ryhov, Sweden.
    Vorkapic, Emina
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Andersson, Roland E.
    County Hospital Ryhov, Sweden.
    Zar, Niklas
    County Hospital Ryhov, Sweden.
    Lofgren, Sture
    County Hospital Ryhov, Sweden.
    Dimberg, Jan
    School Health Science, Sweden.
    Matussek, Andreas
    County Hospital Ryhov, Sweden.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    CD93 gene polymorphism is associated with disseminated colorectal cancer2015In: International Journal of Colorectal Disease, ISSN 0179-1958, E-ISSN 1432-1262, Vol. 30, no 7, p. 883-890Article in journal (Refereed)
    Abstract [en]

    Cluster of differentiation 93 (CD93) is involved in apoptosis and inflammation and has a suggested role in angiogenesis, and all of which are involved in the development and dissemination of cancer. We evaluated the expression of CD93 and the association with two single nucleotide polymorphisms (SNPs), rs2749812 and rs2749817, as possible biomarkers in colorectal cancer (CRC). Tissue levels and plasma levels of CD93 were measured using an enzyme-linked immunosorbent assay (ELISA). Expression of CD93 was determined by immunohistochemistry, western blot and gene expression analysis. Genotype frequencies were established for the SNPs by real-time polymerase chain reaction (PCR), and the association with tumour stage and survival was analysed. Total CD93 levels were 82 % higher (P less than 0.001) in tumours compared to matched normal tissues. Mean levels of soluble CD93 in plasma were 30 % lower (P less than 0.001) in the patients compared to the controls. The T/T genotype of SNP rs2749817 was more common in stage IV patients, with consequently higher risk of CRC death (T/T vs. C/C and C/T; hazard ratio (HR) = 1.73, 95 % confidence interval (CI) = 1.11-2.67, P = 0.014), and was associated with a higher risk of CRC recurrence after radical operation (T/T vs. C/C and C/T; HR = 2.07, CI = 1.22-3.51, P = 0.007). We showed that the T/T genotype of SNP rs2749817 is associated with disseminated cancer at diagnosis and an increased recurrence rate after radical operation. Patients with this genotype may benefit from early identification.

  • 6.
    Vorkapic, Emina
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Dugic, Elma
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Vikingsson, Svante
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Roy, Joy
    Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Mäyränpää, Mikko I.
    Department of Pathology, University of Helsinki, Helsinki, Finland / HUSLAB, Division of Pathology, Meilahti Laboratories of Pathology, Helsinki University Central Hospital, Helsinki, Finland.
    Eriksson, Per
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Imatinib treatment attenuates growth and inflammation of angiotensin II induced abdominal aortic aneurysm2016In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 249, p. 101-109Article in journal (Refereed)
    Abstract [en]

    AbstractBackground Abdominal aortic aneurysm (AAA) is characterized by vascular remodeling with increased infiltration of inflammatory cells and apoptosis/modulation of vascular smooth muscle cells (SMCs). Imatinib is a selective inhibitor of several tyrosine kinases, including PDGF receptors, Abl, and c-kit. The objective of this study was to characterize the potential protective role of imatinib on AAA development and the molecular mechanisms involved. Methods Male ApoE−/− mice were infused with angiotensin (Ang) II (1000 ng/kg/min) for 4 weeks to induce AAA or saline as controls. Daily treatment with 10 mg/kg imatinib, or tap water as control, was provided via gavage for 4 weeks. Results Treatment with imatinib was found to decrease the aortic diameter and vessel wall thickness, mediated by multiple effects. Imatinib treatment in AngII infused mice resulted in a reduced cellular infiltration of CD3ε positive T lymphocytes by 86% and reduced gene expression of mast cell chymase by 50% compared with AngII infused mice lacking imatinib. Gene expression analysis of SMC marker SM22α demonstrated an increase by 48% together with a more intact medial layer after treatment with imatinib as evaluated with SM22α immunostaining. Conclusion Present findings highlight the importance of tyrosine kinase pathways in the development of AAA. Our results show, that imatinib treatment inhibits essential mast cell, T lymphocyte and SMC mediated processes in experimental AAA. Thus, our results support the idea that tyrosine kinase inhibitors may be useful in the treatment of pathological vascular inflammation and remodeling in conditions like AAA.

  • 7.
    Vorkapic, Emina
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Lundberg, Anna M.
    Karolinska University Hospital Solna, Sweden.
    Mayranpaa, Mikko I.
    University of Helsinki, Finland; University of Helsinki, Finland.
    Eriksson, Per
    Karolinska Institute, Sweden.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    TRIF adaptor signaling is important in abdominal aortic aneurysm formation2015In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 241, no 2, p. 561-568Article in journal (Refereed)
    Abstract [en]

    Objective: Abdominal aortic aneurysm (AAA) is characterized by inflammation, loss of smooth muscle cells (SMCs), and degradation of the extracellular matrix in the vessel wall. Innate immune receptors such as Toll-like receptors (TLRs) were recently shown to regulate immunological processes leading to the formation and progression of atherosclerotic plaques as well as to other cardiovascular pathologies. Our aim was to investigate whether blockage of TLR signaling, under the control of TIR domain-containing adaptor protein including IFN-beta (TRIF), could inhibit the inflammatory response and AAA development in mice. Results: In human AAA, an increased TLR3 and TLR4 expression in association with macrophages and T lymphocytes was demonstrated with immunohistochemical analysis. Angiotensin (Ang) II-induced aneurysm formation was significantly reduced by 30% in ApoE(-/-)Trif(-/-) mice compared to ApoE(-/-) mice. Morphologically, AngII-infused ApoE(-/-)Trif(-/-) mice had a more intact cellular and extracellular matrix while ApoE(-/-) mice infused with AngII displayed an increased medial thickness associated with aortic dissection, thrombus formation, and a more disorganized vessel wall. Gene expression analysis of the abdominal aorta revealed a profound decrease of the inflammatory genes CD68 (P less than 0.05), CD11b (P less than 0.05), and TNF-alpha (P less than 0.05) and the protease gene MMP-12 (P less than 0.01) in ApoE(-/-)Trif(-/-) mice compared to ApoE(-/-) mice infused with AngII. Conclusion: Our results suggest that signaling through TRIF is important for the inflammatory response of AngII-induced AAA and that blockage of the TRIF pathway reduces vascular inflammation and protects against AAA formation. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.

  • 8.
    Vorkapić, Emina
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Targeting vascular remodeling in abdominal aortic aneurysm: To identify novel treatment strategies and drug candidates2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Abdominal aortic aneurysm (AAA) is a degenerative weakening of the aortic wall, mainly affecting elderly men with a prevalence of 4.4-7.7 %. AAA is characterized by medial and adventitial inflammatory cell infiltration associated with vascular remodeling of the extracellular matrix proteins such as collagen and elastin and with phenotypic modulation and loss of vascular smooth muscle cells (VSMCs). Although much research has been performed, the precise cellular and molecular pathways behind these processes are still poorly understood. The overall aim of this thesis was to target signaling pathways that affect vascular remodeling of AAA to potentially identify novel strategies and drug candidates for future treatment of aneurysmal diseases. In order to develop our understanding of the pathophysiology of AAA, we used the angiotensin (Ang) II-induced AAA animal model and human biopsies taken at end-stage of disease to recapitulate key aspects of disease formation.

    Innate immune receptors such as toll-like receptors (TLRs) are known to regulate immunological processes leading to the formation and progression of vascular disease including AAA. In paper I, we aimed to investigate the role of TLR signaling under the control of the TRIF adaptor protein in the formation of AAA. Human, aneurysmal aortas displayed increased expression of TLR3 and TLR4 in surface of macrophages and T lymphocytes. AngII-induced aneurysm formation was attenuated in mice lacking the Trif gene  (ApoE-/-Triʃ-/-), and these knockout mice presented with a more intact medial layer together with a reduced inflammatory response by macrophages and T lymphocytes and reduced levels of pro-inflammatory cytokines, chemokines, and proteases. Our results suggest an involvement of TRIF in the pathophysiology of AAA.

    Current management of AAA fully depends on imaging and surgical techniques, and drug-based therapies are still mostly ineffective. In paper II, we aimed to investigate the potential protective role of the tyrosine kinase inhibitor imatinib on the molecular mechanism involved in AAA formation. In AngII-infused ApoE-/-mice, 10 mg/kg imatinib per day affected several key features important in aneurysmal formation, including  preservation of the medial layer of the VSMCs, reduced infiltrations of CD3ε-positive T lymphocytes, and reduced gene expression of mast cell chymase, resulting in decreased aortic diameter and vessel wall thickness. These results highlight the importance of the tyrosine kinase inhibitor imatinib as a potential drug in the treatment of pathological vascular inflammation and remodeling in conditions such as AAA.

    In paper III, we aimed to investigate the role of adiponectin in experimentally induced AAA formation in mice. In mice with elevated adiponectin levels, AAA development was inhibited, and this was associated with reduced inflammatory cell infiltration, reduced medial degeneration of VSMCs and of elastin in the aortic vessel wall together with an improved systemic cytokine profile and the attenuation of periaortic adipose tissue (PVAT) inflammation. These results support the protective effect of adiponectin in the remodeling occurring in the aortic wall and in the prevention of AAA.

    In paper IV, we performed a descriptive study investigating the composition of PVAT adjacent to the aneurysmal aorta. We used immunohistochemistry to identify neutrophils, macrophages, mast cells, and T lymphocytes surrounding necrotic adipocytes in PVAT together with increased gene expression of IL-6 and cathepsin K and S. We also determined the concentrations of pro-inflammatory ceramides in PVAT and found an association to T lymphocytes. These results suggest that inflamed adipose tissue might be a source of proinflammatory cells and mediators that contribute to aortic wall degeneration.

    List of papers
    1. TRIF adaptor signaling is important in abdominal aortic aneurysm formation
    Open this publication in new window or tab >>TRIF adaptor signaling is important in abdominal aortic aneurysm formation
    Show others...
    2015 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 241, no 2, p. 561-568Article in journal (Refereed) Published
    Abstract [en]

    Objective: Abdominal aortic aneurysm (AAA) is characterized by inflammation, loss of smooth muscle cells (SMCs), and degradation of the extracellular matrix in the vessel wall. Innate immune receptors such as Toll-like receptors (TLRs) were recently shown to regulate immunological processes leading to the formation and progression of atherosclerotic plaques as well as to other cardiovascular pathologies. Our aim was to investigate whether blockage of TLR signaling, under the control of TIR domain-containing adaptor protein including IFN-beta (TRIF), could inhibit the inflammatory response and AAA development in mice. Results: In human AAA, an increased TLR3 and TLR4 expression in association with macrophages and T lymphocytes was demonstrated with immunohistochemical analysis. Angiotensin (Ang) II-induced aneurysm formation was significantly reduced by 30% in ApoE(-/-)Trif(-/-) mice compared to ApoE(-/-) mice. Morphologically, AngII-infused ApoE(-/-)Trif(-/-) mice had a more intact cellular and extracellular matrix while ApoE(-/-) mice infused with AngII displayed an increased medial thickness associated with aortic dissection, thrombus formation, and a more disorganized vessel wall. Gene expression analysis of the abdominal aorta revealed a profound decrease of the inflammatory genes CD68 (P less than 0.05), CD11b (P less than 0.05), and TNF-alpha (P less than 0.05) and the protease gene MMP-12 (P less than 0.01) in ApoE(-/-)Trif(-/-) mice compared to ApoE(-/-) mice infused with AngII. Conclusion: Our results suggest that signaling through TRIF is important for the inflammatory response of AngII-induced AAA and that blockage of the TRIF pathway reduces vascular inflammation and protects against AAA formation. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.

    Place, publisher, year, edition, pages
    ELSEVIER IRELAND LTD, 2015
    Keywords
    Vascular disease; Inflammation; Toll-like receptor; Angiontensin II
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-121438 (URN)10.1016/j.atherosclerosis.2015.06.014 (DOI)000360100700035 ()26100679 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [K2013-99X-22231-01-5]

    Available from: 2015-09-18 Created: 2015-09-18 Last updated: 2017-12-04
    2. Imatinib treatment attenuates growth and inflammation of angiotensin II induced abdominal aortic aneurysm
    Open this publication in new window or tab >>Imatinib treatment attenuates growth and inflammation of angiotensin II induced abdominal aortic aneurysm
    Show others...
    2016 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 249, p. 101-109Article in journal (Refereed) Published
    Abstract [en]

    AbstractBackground Abdominal aortic aneurysm (AAA) is characterized by vascular remodeling with increased infiltration of inflammatory cells and apoptosis/modulation of vascular smooth muscle cells (SMCs). Imatinib is a selective inhibitor of several tyrosine kinases, including PDGF receptors, Abl, and c-kit. The objective of this study was to characterize the potential protective role of imatinib on AAA development and the molecular mechanisms involved. Methods Male ApoE−/− mice were infused with angiotensin (Ang) II (1000 ng/kg/min) for 4 weeks to induce AAA or saline as controls. Daily treatment with 10 mg/kg imatinib, or tap water as control, was provided via gavage for 4 weeks. Results Treatment with imatinib was found to decrease the aortic diameter and vessel wall thickness, mediated by multiple effects. Imatinib treatment in AngII infused mice resulted in a reduced cellular infiltration of CD3ε positive T lymphocytes by 86% and reduced gene expression of mast cell chymase by 50% compared with AngII infused mice lacking imatinib. Gene expression analysis of SMC marker SM22α demonstrated an increase by 48% together with a more intact medial layer after treatment with imatinib as evaluated with SM22α immunostaining. Conclusion Present findings highlight the importance of tyrosine kinase pathways in the development of AAA. Our results show, that imatinib treatment inhibits essential mast cell, T lymphocyte and SMC mediated processes in experimental AAA. Thus, our results support the idea that tyrosine kinase inhibitors may be useful in the treatment of pathological vascular inflammation and remodeling in conditions like AAA.

    Keywords
    Abdominal aortic aneurysm, Vascular inflammation, Imatinib, Angiotensin II
    National Category
    Cell and Molecular Biology Physiology
    Identifiers
    urn:nbn:se:liu:diva-127501 (URN)10.1016/j.atherosclerosis.2016.04.006 (DOI)000376505800016 ()27085160 (PubMedID)
    Available from: 2016-04-28 Created: 2016-04-28 Last updated: 2018-01-10Bibliographically approved
    3. Inflammatory cells, ceramides, and expression of proteases in perivascular adipose tissue adjacent to human abdominal aortic aneurysms
    Open this publication in new window or tab >>Inflammatory cells, ceramides, and expression of proteases in perivascular adipose tissue adjacent to human abdominal aortic aneurysms
    Show others...
    2017 (English)In: Journal of Vascular Surgery, ISSN 0741-5214, E-ISSN 1097-6809, Vol. 65, no 4, p. 1171-Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Abdominal aortic aneurysm (AAA) is a deadly irreversible weakening and distension of the abdominal aortic wall. The pathogenesis of AAA remains poorly understood. Investigation into the physical and molecular characteristics of perivascular adipose tissue (PVAT) adjacent to AAA has not been done before and is the purpose of this study.

    METHODS AND RESULTS: Human aortae, periaortic PVAT, and fat surrounding peripheral arteries were collected from patients undergoing elective surgical repair of AAA. Control aortas were obtained from recently deceased healthy organ donors with no known arterial disease. Aorta and PVAT was found in AAA to larger extent compared with control aortas. Immunohistochemistry revealed neutrophils, macrophages, mast cells, and T-cells surrounding necrotic adipocytes. Gene expression analysis showed that neutrophils, mast cells, and T-cells were found to be increased in PVAT compared with AAA as well as cathepsin K and S. The concentration of ceramides in PVAT was determined using mass spectrometry and correlated with content of T-cells in the PVAT.

    CONCLUSIONS: Our results suggest a role for abnormal necrotic, inflamed, proteolytic adipose tissue to the adjacent aneurysmal aortic wall in ongoing vascular damage.

    National Category
    Surgery Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:liu:diva-126051 (URN)10.1016/j.jvs.2015.12.056 (DOI)000402625400035 ()26960947 (PubMedID)
    Available from: 2016-03-11 Created: 2016-03-11 Last updated: 2018-05-07
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